Direct rAAV SOX9 administration for durable articular cartilage repair with delayed terminal differentiation and hypertrophy in vivo
Direct rAAV SOX9 administration for durable articular cartilage repair with delayed terminal differentiation and hypertrophy in vivo
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DOI：
10.1007/s00109-012-0978-9
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发表时间：
2013-05-01
影响因子：
4.7
通讯作者：
Madry, Henning
中科院分区：
文献类型：
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作者：
Cucchiarini, Magali;Orth, Patrick;Madry, Henning
直接基因转移策略在关节软骨缺损的治疗中具有广阔的应用前景。在这里，我们测试了重组腺相关病毒（rAAV） SOX9载体在体内增强软骨损伤修复的能力。将候选构建体提供给兔膝关节骨软骨缺损vis-A -vis control （lacZ）载体处理和修复组织相关细胞（间充质干细胞、软骨细胞）。在病变内（长达16周）和体外细胞（21天）中观察到高效、长期的转基因表达。SOX9载体能够刺激体外和体内的生物活性。体内SOX9治疗耐受性良好，导致软骨修复过程改善，主要基质成分的产生增强。值得注意的是，rAAV SOX9的应用延缓了新形成软骨的过早终末分化和肥大，这可能是由于SOX9对该区域RUNX2和β -catenin成骨表达的不同影响。最引人注目的是，SOX9治疗改善了缺损软骨下骨的重建，可能是由于RUNX2在该位置的表达增加。这些发现表明直接rAAV基因递送作为治疗软骨病变的有效工具的潜力。
Direct gene transfer strategies are of promising value to treat articular cartilage defects. Here, we tested the ability of a recombinant adeno-associated virus (rAAV) SOX9 vector to enhance the repair of cartilage lesions in vivo. The candidate construct was provided to osteochondral defects in rabbit knee joints vis-A -vis control (lacZ) vector treatment and to cells relevant of the repair tissue (mesenchymal stem cells, chondrocytes). Efficient, long-term transgene expression was noted within the lesions (up to 16 weeks) and in cells in vitro (21 days). Administration of the SOX9 vector was capable of stimulating the biological activities in vitro and over time in vivo. SOX9 treatment in vivo was well tolerated, leading to improved cartilage repair processes with enhanced production of major matrix components. Remarkably, application of rAAV SOX9 delayed premature terminal differentiation and hypertrophy in the newly formed cartilage, possible due to contrasting effects of SOX9 on RUNX2 and beta-catenin osteogenic expression in this area. Most strikingly, SOX9 treatment improved the reconstitution of the subchondral bone in the defects, possibly due to an increase in RUNX2 expression in this location. These findings show the potential of direct rAAV gene delivery as an efficient tool to treat cartilage lesions.